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Stem Cell Investigation 2023The endothelial-to-mesenchymal transition (EndoMT) is a crucial process in cardiovascular development and disorders. Cardiac fibrosis, characterized by excessive...
BACKGROUND
The endothelial-to-mesenchymal transition (EndoMT) is a crucial process in cardiovascular development and disorders. Cardiac fibrosis, characterized by excessive collagen deposition, occurs in heart failure, leading to the organ remodeling. Embryonic signaling pathways such as bone morphogenetic protein 2 (BMP2) and Notch are involved in its regulation. However, the interplay between these pathways in EndoMT remains unclear.
METHODS
This study investigates the downstream targets of Notch and BMP2 and their effect on EndoMT markers in cardiac mesenchymal cells (CMCs) and human umbilical vein endothelial cells (HUVECs). We transduced cell cultures with vectors carrying intracellular domain of NOTCH1 () and/or and evaluated gene expression and activation of EndoMT markers.
RESULTS
The results suggest that the Notch and BMP2 signaling pathways have common downstream targets that regulate EndoMT. The activation of BMP2 and Notch is highly dependent on cell type, and co-cultivation of CMCs and HUVECs produced opposing cellular responses to target gene expression and α-smooth muscle actin (α-SMA) synthesis.
CONCLUSIONS
The balance between Notch and BMP2 signaling determines the outcome of EndoMT and fibrosis in the heart. The study's findings highlight the need for further research to understand the interaction between Notch and BMP2 in the heart and develop new therapeutic strategies for treating cardiac fibrosis.
PubMed: 37842185
DOI: 10.21037/sci-2023-019 -
The Journals of Gerontology. Series A,... Oct 2023Machine learning (ML) models can be used to predict future frailty in the community setting. However, outcome variables for epidemiologic data sets such as frailty...
BACKGROUND
Machine learning (ML) models can be used to predict future frailty in the community setting. However, outcome variables for epidemiologic data sets such as frailty usually have an imbalance between categories, that is, there are far fewer individuals classified as frail than as nonfrail, adversely affecting the performance of ML models when predicting the syndrome.
METHODS
A retrospective cohort study with participants (50 years or older) from the English Longitudinal Study of Ageing who were nonfrail at baseline (2008-2009) and reassessed for the frailty phenotype at 4-year follow-up (2012-2013). Social, clinical, and psychosocial baseline predictors were selected to predict frailty at follow-up in ML models (Logistic Regression, Random Forest [RF], Support Vector Machine, Neural Network, K-nearest neighbor, and Naive Bayes classifier).
RESULTS
Of all the 4 378 nonfrail participants at baseline, 347 became frail at follow-up. The proposed combined oversampling and undersampling method to adjust imbalanced data improved the performance of the models, and RF had the best performance, with areas under the receiver-operating characteristic curve and the precision-recall curve of 0.92 and 0.97, respectively, specificity of 0.83, sensitivity of 0.88, and balanced accuracy of 85.5% for balanced data. Age, chair-rise test, household wealth, balance problems, and self-rated health were the most important frailty predictors in most of the models trained with balanced data.
CONCLUSIONS
ML proved useful in identifying individuals who became frail over time, and this result was made possible by balancing the data set. This study highlighted factors that may be useful in the early detection of frailty.
Topics: Aged; Humans; Middle Aged; Frailty; Cohort Studies; Longitudinal Studies; Frail Elderly; Independent Living; Bayes Theorem; Retrospective Studies; Machine Learning
PubMed: 37209408
DOI: 10.1093/gerona/glad127 -
Research Square Sep 2023Stroke is a major cause of morbidity and mortality, and its incidence increases with age. While acute therapies for stroke are currently limited to intravenous...
BACKGROUND
Stroke is a major cause of morbidity and mortality, and its incidence increases with age. While acute therapies for stroke are currently limited to intravenous thrombolytics and endovascular thrombectomy, recent studies have implicated an important role for the gut microbiome in post-stroke neuroinflammation. After stroke, several immuno-regulatory pathways, including the aryl hydrocarbon receptor (AHR) pathway, become activated. AHR is a master regulatory pathway that mediates neuroinflammation. Among various cell types, microglia (MG), as the resident immune cells of the brain, play a vital role in regulating post-stroke neuroinflammation and antigen presentation. Activation of AHR is dependent on a dynamic balance between host-derived and microbiota-derived ligands. While previous studies have shown that activation of MG AHR by host-derived ligands, such as kynurenine, is detrimental after stroke, the effects of post-stroke changes in microbiota-derived ligands of AHR, such as indoles, is unknown. Our study builds on the concept that differential activation of MG AHR by host-derived versus microbiome-derived metabolites affects outcomes after ischemic stroke. We examined the link between stroke-induced dysbiosis and loss of essential microbiota-derived AHR ligands. We hypothesize that restoring the balance between host-derived (kynurenine) and microbiota-derived (indoles) ligands of AHR is beneficial after stroke, offering a new potential avenue for therapeutic intervention in post-stroke neuroinflammation.
METHOD
We performed immunohistochemical analysis of brain samples from stroke patients to assess MG AHR expression after stroke. We used metabolomics analysis of plasma samples from stroke and non-stroke control patients with matched comorbidities to determine the levels of indole-based AHR ligands after stroke. We performed transient middle cerebral artery occlusion (MCAO) in aged (18 months) wild-type (WT) and germ-free (GF) mice to investigate the effects of post-stroke treatment with microbiota-derived indoles on outcome. To generate our results, we employed a range of methodologies, including flow cytometry, metabolomics, and 16S microbiome sequencing.
RESULTS
We found that MG AHR expression is increased in human brain after stroke and after oxygen-glucose deprivation and reperfusion (OGD/R). Microbiota-derived ligands of AHR are decreased in the human plasma at 24 hours after ischemic stroke. Kynurenine and indoles exhibited differential effects on aged WT MG survival after OGD/R. We found that specific indole-based ligands of AHR (indole-3-propionic acid and indole-3-aldehyde) were absent in GF mice, thus their production depends on the presence of a functional gut microbiota. Additionally, a time-dependent decrease in the concentration of these indole-based AHR ligands occurred in the brain within the first 24 hours after stroke in aged WT mice. Post-stroke treatment of GF mice with a cocktail of microbiota-derived indole-based ligands of AHR regulated MG-mediated neuroinflammation and molecules involved in antigen presentation (increased CD80, MHC-II, and CD11b). Post-stroke treatment of aged WT mice with microbiota-derived indole-based ligands of AHR reduced both infarct volume and neurological deficits at 24 hours.
CONCLUSION
Our novel findings provide compelling evidence that the restoration of a well-balanced pool of host-derived kynurenine-based and microbiota-derived indole-based ligands of AHR holds considerable therapeutic potential for the treatment of ischemic stroke.
PubMed: 37790313
DOI: 10.21203/rs.3.rs-3143015/v1 -
Pharmaceuticals (Basel, Switzerland) Sep 2023Balancing the therapeutic advantages of a medicine with its possible risks and side effects is an important part of medical practice and drug regulation. When a drug is... (Review)
Review
Balancing the therapeutic advantages of a medicine with its possible risks and side effects is an important part of medical practice and drug regulation. When a drug is designed to treat a particular disease or medical condition ends up causing additional risks or side effects that lead to the development of other serious health problems, it can have detrimental consequences for patients. This article explores the correlation between persistent proton pump inhibitor (PPI) use and hypertension, a common cardiovascular ailment. While PPIs are beneficial in treating various gastrointestinal problems, their availability without a prescription has resulted in self-medication and long-term use without medical monitoring. Recent findings have revealed a link between long-term PPI usage and increased cardiovascular risks, particularly hypertension. This study investigates the intricate mechanisms underlying PPI's effects, focusing on potential pathways contributing to hypertension, such as endothelial dysfunction, disruption of nitric oxide bioavailability, vitamin B deficiency, hypocalcemia, and hypomagnesemia. The discussion explains how long-term PPI use can disrupt normal endothelial function, vascular control, and mineral balance, eventually leading to hypertension. The article emphasizes the significance of using PPIs with caution and ongoing research to better understand the implications of these medications on cardiovascular health.
PubMed: 37895858
DOI: 10.3390/ph16101387 -
Experimental Gerontology Sep 2023The purpose of this study was to prospectively investigate the relationship between new falls and the balancing ability of older adults aged ≥80 years who are...
OBJECTIVE
The purpose of this study was to prospectively investigate the relationship between new falls and the balancing ability of older adults aged ≥80 years who are independent and evaluate the validity of the assessment tools as a predictor of falls.
METHODS
We enrolled a total of 160 participants (104 males and 56 females) aged 80 years or older. During the 12 months of observation, we investigated underlying diseases and drug use and performed a comprehensive geriatric assessment (including self-care ability, muscle strength, action ability, cognition, emotional state, and other aspects), as well as computerized dynamic posturography to assess balance and gait functions. We further analyzed the relationship between new falls and multiple internal risk factors.
RESULTS
A total of 159 participants were included for statistical analysis, and there were 108 new falls among the 59 participants. Fall history and visual preference (PREF) scores on the sensory integration test showed a positive correlation with new falls. The composite equilibrium score (SOTcom), left total hip bone mineral density, left directional control, and end point deviation were all found to be negatively correlated with new falls (P < 0.05). The cut-off point of the timed "up and go" test (TUG) in predicting new falls in this cohort was >12.03 s, with a sensitivity of 78.0 %, a specificity of 51.5 %, and an AUC of 0.667 (P < 0.001, 95 % CI: 0.567-0.721). The cut-off point of SOTcom in predicting new falls was ≤52, with a sensitivity of 40.7 %, a specificity of 84.0 %, and an AUC of 0.606 (P = 0.028, 95 % CI: 0.525-0.682).
CONCLUSIONS
The decline of balance sensory input function (mainly vestibular and visual sense), skeletal muscle motor function, and related postural control ability constituted the main risk factors for new falls in older adults who were independent. The combined use of TUG and SOT was useful in further improving the accuracy of predicting new falls in this population and providing a direction for effective intervention and rehabilitation measures.
Topics: Male; Aged; Female; Humans; Prospective Studies; Geriatric Assessment; Physical Therapy Modalities; Risk Factors; Gait; Postural Balance
PubMed: 37473970
DOI: 10.1016/j.exger.2023.112259 -
Clinical Nutrition (Edinburgh, Scotland) Nov 2023This review summarises some of my work on fluid and electrolyte balance over the past 25 years and shows how the studies have influenced clinical practice. Missing... (Review)
Review
This review summarises some of my work on fluid and electrolyte balance over the past 25 years and shows how the studies have influenced clinical practice. Missing pieces in the jigsaw are filled in by summarising the work of others. The main theme is the biochemical, physiological and clinical problems caused by inappropriate use of saline solutions including the hyperchloraemic acidosis caused by 0.9% saline. The importance of accurate and near-zero fluid balance in clinical practice is also emphasised. Perioperative fluid and electrolyte therapy has important effects on clinical outcome in a U-shaped dose response fashion, in which excess or deficit progressively increases complications and worsens outcome. Salt and water overload, with weight gain in excess of 2.5 kg worsens surgical outcome, impairs gastrointestinal function and increases the risk of anastomotic dehiscence. Hyperchloraemic acidosis caused by overenthusiastic infusion of 0.9% saline leads to adverse outcomes and dysfunction of many organ systems, especially the kidney. Salt and water deficit causes similar adverse effects as fluid overload at the cellular level and also leads to worse outcomes. Serum albumin is shown to be affected mainly by dilution and inflammation and is not a good nutritional marker. These findings have been incorporated in the British consensus Guidelines on Intravenous Fluid Therapy for Adult Surgical Patients (GIFTASUP) and National Institute for Health and Care Excellence (NICE) guidelines on intravenous fluid therapy in adults in hospital and are helping change clinical practice and improve outcomes.
Topics: Adult; Humans; Saline Solution; Fluid Therapy; Water-Electrolyte Balance; Sodium Chloride; Acidosis; Water
PubMed: 37820519
DOI: 10.1016/j.clnu.2023.09.029 -
BMJ Open Dec 2023Fear of fall is experienced by the elderly irrespective of the presence or absence of history of fall. Falls contribute to injuries that culminate in hospitalisation... (Randomized Controlled Trial)
Randomized Controlled Trial
INTRODUCTION
Fear of fall is experienced by the elderly irrespective of the presence or absence of history of fall. Falls contribute to injuries that culminate in hospitalisation that incur unwarranted medical expenses. Yoga is unique to Indian cultural practices, with a potential to enhance proprioception. It increases self-body awareness, ultimately improving the balancing capacity of older adults. Thus, the objective of this study is to compare the effect of yoga therapy in the study and control groups at 12 weeks from the baseline.
METHODS AND ANALYSIS
This study is designed as an open-label, randomised controlled trial (1:1) with a sample size of 62 elderly patients more than or equal to 60 years of age. Participation of either sex, male or female with a fear of fall will be considered. Two randomised groups of 31 participants each will receive standard therapy for their primary diseases as per the local, national or international guidelines. However, participants in the intervention arm will receive additional structured yoga therapy sessions. The primary objective of this study is to assess and compare the change in fear of fall score of participants in each group using Falls Efficacy Scale (FES) and Berg Balance Scale (BBS) at 12 weeks versus baseline. The secondary endpoint will assess the change in the quality of life of participants at 3 months compared with the baseline.Data will be gathered, entered into Microsoft Excel and further analysed by R software (V.4.3.0). Changes in FES-Intervention and BBS of two groups will be compared either by Student's t-test for parametric data or Mann-Whitney U test for non-parametric data. Statistical significance will be considered if p<0.05 at 95% confidence level.
ETHICS AND DISSEMINATION
Ethical approval for this study protocol (version 1.0, 22 April 2022) was obtained from the institute ethics committee (AIIMS/IEC/22/195).
TRIAL REGISTRATION NUMBER
CTRI/2022/06/043287.
Topics: Humans; Male; Female; Aged; COVID-19; SARS-CoV-2; Yoga; Quality of Life; Fear
PubMed: 38151281
DOI: 10.1136/bmjopen-2022-070540 -
Materials Today. Bio Dec 2023Bone regeneration heavily relies on bone marrow mesenchymal stem cells (BMSCs). However, recruiting endogenous BMSCs for in situ bone regeneration remains challenging....
Bone regeneration heavily relies on bone marrow mesenchymal stem cells (BMSCs). However, recruiting endogenous BMSCs for in situ bone regeneration remains challenging. In this study, we developed a novel BMSC-aptamer (BMSC-apt) functionalized hydrogel (BMSC-aptgel) and evaluated its functions in recruiting BMSCs and promoting bone regeneration. The functional hydrogels were synthesized between maleimide-terminated 4-arm polyethylene glycols (PEG) and thiol-flanked PEG crosslinker, allowing rapid in situ gel formation. The aldehyde group-modified BMSC-apt was covalently bonded to a thiol-flanked PEG crosslinker to produce high-density aptamer coverage on the hydrogel surface. In vitro and in vivo studies demonstrated that the BMSC-aptgel significantly increased BMSC recruitment, migration, osteogenic differentiation, and biocompatibility. In vivo fluorescence tomography imaging demonstrated that functionalized hydrogels effectively recruited DiR-labeled BMSCs at the fracture site. Consequently, a mouse femur fracture model significantly enhanced new bone formation and mineralization. The aggregated BMSCs stimulated bone regeneration by balancing osteogenic and osteoclastic activities and reduced the local inflammatory response via paracrine effects. This study's findings suggest that the BMSC-aptgel can be a promising and effective strategy for promoting in situ bone regeneration.
PubMed: 38024846
DOI: 10.1016/j.mtbio.2023.100854 -
Medicina (Kaunas, Lithuania) Oct 2023: Type 2 diabetes mellitus (T2DM) is a chronic condition recognized as the inability to maintain glucose homeostasis, typically presenting with insulin resistance and...
: Type 2 diabetes mellitus (T2DM) is a chronic condition recognized as the inability to maintain glucose homeostasis, typically presenting with insulin resistance and systemic inflammation. With the prevalence of T2DM and major risk factors, such as prediabetes and obesity, increasing each year, the need to address risk factor reduction strategies is crucial. : Twenty-two men and women, overweight-to-obese adults (BMI mean: 26.1-31.6) (age range mean: 44.6-51.8) with T2DM, indicators of prediabetes, or who were metabolically healthy, participated in Cal Poly's Nutrition and Exercise in Type 2 Diabetes (CPNET) study. There were no significant differences in terms of age, BMI, or sex distribution among the groups at the baseline. This study's protocol included following a Mediterranean-style diet, the daily consumption of a high-quality whey protein supplement, and physical activity recommendations for 16 weeks. Body composition data, via dual-energy X-ray absorptiometry (DXA), and fasting blood samples were collected at the baseline and following the intervention. Due to restrictions associated with the outbreak of the COVID-19 pandemic, only 13 of the 22 participants who started this study were able to return for the second data collection to complete this study following the 16-week intervention. : The prediabetic and T2DM groups exhibited reductions in their fasting plasma glucose (12.0 mg/dL reduction in the prediabetic group; 19.6 mg/dL reduction in the T2DM group) to that of normal and prediabetic levels, respectively, while the T2DM group also demonstrated improvement in their hemoglobin A1c (reduced from 6.8% to 6.0%) to prediabetic levels. Additionally, the metabolically healthy, overweight group exhibited significant improvements in adiposity, while the obese prediabetic and T2DM groups showed non-significant improvements in all the measured metrics of body composition. No significant changes were observed in the inflammatory biomarkers (-values ranged from 0.395 to 0.877). : Collectively, our results suggest that adherence to a well-balanced, nutritious diet and activity may improve the parameters of glycemic control and provide benefits to body composition that help to manage and prevent the development of T2DM. Our study was able to yield significant findings signifying that the effects of a Mediterranean-style diet are observed even for a more conservative sample size.
Topics: Adult; Male; Humans; Female; Diabetes Mellitus, Type 2; Prediabetic State; Overweight; Pandemics; Obesity; Diet, Mediterranean; Blood Glucose
PubMed: 37893600
DOI: 10.3390/medicina59101882